Studies highlight new drug targets or compounds for acute myeloid leukemia

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Preclinical data unveiled across four studies presented at the 57th annual meeting of the American Society of Hematology highlight four potential treatment opportunities for acute myeloid leukemia (AML), a blood cancer accounting for approximately 20 percent of all childhood leukemias and 32 percent of adult leukemias. The four studies, led by investigators from Dana-Farber/Boston Children's Cancer and Blood Disorders Center, represent significant progress in seeking out and targeting multiple vulnerabilities within AML cells, including aspects of the cells' metabolism, internal communications and ability to transport proteins between different compartments.

The overall survival rate for pediatric AML is between 60 and 70 percent — above 80 percent for some specific subtypes. For adult AML, the numbers are far worse; overall survival is 45 percent, and goes down dramatically with age. Both pediatric and adult AML frequently relapse, generally in a treatment-resistant form. Thus, there is a significant need for treatment options that can improve the survival rate and can effectively treat patients with relapses when they do occur.

"When you look at overall survival and how we treat most patients with AML, things have changed remarkably little in the last 20 years," said Kimberly Stegmaier, MD, a pediatric hematologist/oncologist at Dana-Farber/Boston Children's and senior investigator on three of the four studies. "We still use older chemotherapy drugs in both adults and children that are very toxic, and we have quite a way to go to cure all patients with this disease.

"In the last few years, target and molecule discovery have really accelerated," Stegmaier continued, "which for continued progress in treating patients with AML is essential. “To make headway against those forms of AML resistant to current therapy, we will need treatments that are fundamentally different from those in our current armamentarium.”

The four Dana-Farber/Boston Children's AML studies, each of which focuses on a different aspect of AML biology, are:

The targets and molecules being presented represent just a few of the opportunities created by the last decade’s efforts to tease apart the complicated genomics of cancer in general, and AML in particular.

"AML led the genomic sequencing revolution in cancer. The first cancer genome sequenced was from a patient with AML," Stegmaier explained. "We have learned a great deal since then. There are a number of new treatment approaches being tested in the clinic that are very exciting. These abstracts reflect just a few of the emerging targets of great interest."

For a full list of co-authors and their affiliated institutions for each of the abstracts, please visit

  • "Nuclear export inhibitor KPT-8602 is highly active against leukemic blasts and leukemia-initiating cells in patient-derived xenograft models of AML" (abstract 326). Selinexor, a member of a class of drugs called selective inhibitors of nuclear export (SINE), which prevent cancer cells from transferring proteins out of the nucleus, is showing promising results in both adult and pediatric clinical trials for relapsed or drug-resistant AML. In vivo preclinical studies by Dana-Farber/Boston Children's A. Thomas Look, MD, and colleagues suggest that a next generation SINE compound, KPT-8602, may outperform selinexor in tolerability and ability to target both malignant AML cells and AML leukemia-initiating cells, which can dodge current treatments and fuel relapses.
  • "Targeting MTHFD2 in acute myeloid leukemia" (abstract 443). MTHFD2 is an enzyme involved in folate metabolism in the mitochondria of cells. This enzyme is present in much greater amounts in cancer cells, including AML cells, than in healthy ones. Through a series of in vitro and in vivo experiments, Stegmaier and her colleagues found that they could reduce AML cell growth by shutting off MTHFD2, suggesting that the enzyme could be a useful target for drug development.
  • "Identification of a first in class GSK3-alpha selective inhibitor as a new differentiation therapy for AML" (abstract 870). AML is characterized by an overabundance of cells that are stuck in an immature state. GSK3-alpha is a signaling molecule that controls aspects of cell metabolism that has previously shown promise as an AML target. To date, however, no one has developed compounds with good drug-like properties specifically against this enzyme. Stegmaier and her colleagues report on the promising preclinical in vitro data of a new compound called BRD0705 that blocks GSK3-alpha, showing that the compound forces AML cells to mature and stop growing.
  • "Identification of CKMT1B as a new target in EVI1-positive AML" (abstract 3674). AML patients whose cancer cells produce an excess of a transcription factor called EVI-1 fare relatively poorly. Stegmaier and her colleagues report that by systematically investigating the genes regulated by EVI-1, they found a connection between this factor and a metabolic protein called CKMT1B. In vitro and in vivo experiments suggest that EVI1-overexpressing AML cells must also overproduce CKMT1B in order to survive. Thus, they note, CKMT1B may be a useful target for treating this high-risk subtype of AML.

News Category
Acute Myeloid - AML
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